This NIAMS K08 Proposal seeks to provide a clinician-scientist career development opportunity for a promising junior orthopaedic shoulder surgeon with clinical expertise in reconstructive shoulder surgeries. The candidate had research training in shoulder animal experiments during medical school education and residency. The Mentoring and Research Support Committee is ready to provide rigorous guidance for learning multi- disciplinary mechanistic research knowledge and skills that will be most critical for the candidate's development into an independent orthopaedic surgeon scientist. The candidate has strong institutional support with protected research time. Rotator cuff disorders are some of the most common musculoskeletal disorders, yet treatments need further improvement. Scientific discoveries about rotator cuff disorders can be applied to other inflammatory, degenerative, or traumatic disorders in different anatomic locations. Our research project was deliberately chosen to provide training opportunities that will lead to clinically impactful discoveries, thereby fulfilling all necessary elements of the most successful K08 Award requirements. The shoulder joint is the most mobile joint in the human body, steered by a rotator cuff consisting of tendons arising from the scapula and inserting in a tight region on the top end of the humerus. As a result, the rotator cuff is vulnerable to wear-and-tear of the tendons and inflammation of the bursa, resulting in shoulder pain and dysfunction. Our long-range scientific goal is to establish a molecular therapeutic approach for the treatment of rotator cuff disorders. We can then apply this therapeutic approach to treat other inflammatory disorders in the musculoskeletal system. Our Preliminary Data showed that inflamed human rotator cuff tissues and cells express higher levels of cytokines and chemokines compared to normal rotator cuff tissues. One of the most striking inflammatory mediators is stromal cell derived factor-1 (SDF-1), which is a chemokine responsible for mobilizing inflammatory cells bearing CXCR4/7, a specific receptor for SDF-1. We have established rat rotator cuff tear models that simulate human rotator cuff inflammation. Our central hypothesis is that SDF-1/CXCR4/7 targeting mitigates rotator cuff inflammation and promotes healing of the tendon repair around the shoulder joint. We will conduct rigorous scientific experiments to accomplish the following two Specific Aims. (1) To determine whether SDF-1/CXCR4/7 mediates recruitment of inflammatory cells, cytokine expression, and M1/M2 macrophage polarization at the site of tendon-bursal cell interactions in vitro. (2) To determine whether SDF-1/CXCR4/7 targeting reduces inflammation and enhances repair of torn rotator cuff tendons in vivo. Our proposal is impactful in the era of Precision Medicine because we are introducing a new therapeutic paradigm for shoulder disorders by targeting SDF-1 or other key mediators of inflammation with locally delivered inhibitors. The proposed study should provide rigorous training in innovative mechanistic research that can lead to the development of scientific independency.